Ultrastructural Basis of Neurochemical Measures in Brain

描述(申请人提供)：多巴胺是中枢神经系统中一种非常重要的神经递质，在认知、运动控制和情绪调节方面发挥着核心作用。中枢多巴胺系统的功能障碍与许多疾病有关，包括帕金森氏症、精神分裂症、注意力缺陷多动障碍和药物滥用。脑内细胞外多巴胺浓度的病理改变通常被认为是多巴胺能功能障碍的标志，这使得定量测定活体脑内细胞外多巴胺浓度成为一个非常重要的目标。然而，用多巴胺敏感的探针穿透活的脑组织会造成创伤后果，可能会改变脑多巴胺系统的状态，抑制多巴胺的定量测定。减少体内测量相关创伤的一种策略是通过采用安培和伏安微电极技术来减小探针的尺寸。这项提案将调查微电极带来的创伤减少是否能够从根本上对大脑多巴胺系统有新的理解。目的1将检测缺乏多巴胺转运体的转基因小鼠的细胞外多巴胺浓度，以检验先前关于这些过度活跃的动物表现出细胞外多巴胺水平升高的迹象被与脑损伤相关的不确定性所混淆的假设。目的2将验证这一假说，即大鼠纹状体中的多巴胺和谷氨酸相互作用涉及神经递质在植入的伏安法和安培法微电极微米距离内的多巴胺和谷氨酸末端之间的扩散。AIM 3将评估与伏安微电极相关的应激和神经胶质激活。并且，Aim 4将评估微电极植入部位周围血管床的破坏作为穿透伤的潜在机制。总的来说，这些研究将确定与活体多巴胺测量相关的穿透损伤的程度、时间进程和性质，并表明减少测量损伤可以从根本上重新理解多巴胺系统在正常大脑功能和与大脑疾病相关的功能障碍中的作用。

DESCRIPTION (provided by applicant): Dopamine is a highly significant neurotransmitter in the central nervous system, playing a central role in cognition, motor control, and the regulation of emotion. Dysfunction in central dopamine systems is implicated in a number of disorders, including Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and substance abuse. Pathological alterations in the extracellular concentration of dopamine in the brain are generally viewed as the hallmark of dopaminergic dysfunction, which makes the quantitative determination of extracellular dopamine concentrations in the living brain a highly significant objective. However, the penetration of living brain tissue with dopamine-sensitive probes has traumatic consequences that can alter the state of brain dopamine systems and inhibit quantitative dopamine determination. One strategy for diminishing the trauma associated with in vivo measurements is to decrease the size of the probes by adopting amperometric and voltammetric microelectrode technologies. This proposal will investigate whether the diminished trauma associated with microelectrodes enables fundamentally new understanding of brain dopamine systems. Aim 1 will examine extracellular dopamine concentrations in transgenic mice lacking the dopamine transporter to test the hypothesis that previous indications that these hyperactive animals exhibit elevated extracellular dopamine levels were confounded by the uncertainty associated with brain trauma. Aim 2 will test the hypothesis that dopamine:glutamate interactions in the rat striatum involve the diffusion of neurotransmitters between closely apposed dopamine and glutamate terminals located within micrometer distances of implanted voltammetric and amperometric microelectrodes. Aim 3 will evaluate stress and glial activation associated with voltammetric microelectrodes. And, Aim 4 will evaluate disruption of the vascular bed surrounding microelectrode implantation sites as a potential mechanism underlying penetration trauma. Collectively, these studies will establish the extent, time course, and nature of penetration injury associated with in vivo dopamine measurements and show that diminished measurement-injury enables fundamentally new understanding of the role of dopamine systems in normal brain function and the dysfunction associated with brain disorders.